Patent Application
20070281362
The invention relates to the detection of nitric oxide, NO, in a gas mixture, such as produced during the respiratory cycle of a living organism, so that it becomes possible to determine whether the current lung function belonging to a living organism is normal, or deviates from a predetermined normal level.
It is known that alveolar cells and the respiratory tract epithelium produce endogenous nitric oxide and that this nitric oxide is secreted into the air in the respiratory ducts and/or lungs. This portion of secreted nitric oxide can thus be measured in exhaled air.
Further it is known that an evaluation of the production of endogenous nitric oxide in the lungs and respiratory ducts provides a measurement of the condition and/or function of the lungs and respiratory ducts, i.e. the lungs' condition or function.
It is further observed that in the case of inflammatory lung diseases, such as asthma and alveolitis, the nitric oxide concentration of the exhaled air is higher than normal, since the nitric oxide concentration has increased because of the inflammation. The nitric oxide concentration can thus be used as an indicator of an inflammation in the lungs and of inflammatory diseases, such as asthma or any allergic condition resulting in an inflammation of the lungs and/or respiratory tract.
Asthma constitutes a serious and growing global health problem. Nowadays, about 25 million people in Europe suffer from asthma.
Respiratory gas analysis is a simple, non-invasive method, which can be used for clinical routing measurement of inflammation.
At present exhaled breath analysis is performed only in the function laboratories of medical centers, using chemiluminescent analyzers. These NO analyzers utilize a photochemical reaction between NO and ozone:
NO+O3→NO2(and NO2*)+O2.
NO2*→NO2+hv.
Approximately 10-20% of the NO2 formed is produced in an electronically excited state (NO2*), undergoing a transition to the ground state thereby emitting light. Light is emitted in the wavelength range of 590-2600 nm, and its intensity is proportional to the mass flow rate of NO through the reaction chamber. The detection limit for NO is approximately 1 ppb, which is sufficient considering the levels of exhaled NO in subjects with a normal or abnormal physiology (0-200 ppb). The disadvantages of chemiluminescent analyzers for NO detection are that they are relatively expensive (typically $40.000) and that the equipment is bulky (e.g. not portable). These aspects make chemiluminescent analyzers less attractive for use at the home (in the case of personal health monitoring) or by family practitioners. Therefore, it would be very advantageous to have a NO sensing device which is relatively low-cost and miniaturized so that it can be used for instance in the form of a disposable device for personal health monitoring.
Such a process and device, as well as a sensor to be used in said device, have now been found: they are more specifically based on the use of an organic semi-conducting compound.
The invention thus relates, in a first aspect, to the use of an organic semi-conducting compound for detecting NO.
Generally, detectors for sensing gases using organic semi-conducting compounds are known, and these are often referred to as electronic noses. However, no specific examples to detect NO have been described in the literature. Furthermore, also inorganic semi-conducting compounds are used as gas detectors, and a specific example to detect NO is known from B. Fruhberger et al., Sensors and Actuators B76 (2001), 226-234. This sensor is based on a WO3 thin film chemiresistive sensor element, operating at elevated temperatures (250° C.). This sensor element, however, is not specifically sensitive to NO, therefore additional filters are needed to measure NO in a complex gas mixture such as the human breath.
The present invention deals with an organic semi-conducting compound which is in itself able to react with nitric oxide. Therefore, in principle no extra filters are needed and the sensor can operate at ambient temperatures.
Preferred embodiments of the present use are claimed in claims 2-4.
It is observed that the use of thiophenes as a conducting polymer for the detection of a gas in so-called electronic nose conductivity sensors is mentioned per se in WO02/44698. The use of any thiophene for detecting nitric oxide, NO, is nevertheless not mentioned or suggested in this reference.
In the present use, pentacene is the preferred semi-conducting compound because it has the advantage that it is non-reactive towards water and oxygen, which are both main constituents of (exhaled) air.
The present invention relates in a second aspect to a process for measuring the amount of NO in a gas mixture containing NO, wherein said amount of NO is measured by using an organic semi-conducting compound, the electrical property of which changes upon reaction with NO, said change being utilized as a direct or indirect measure for the amount of NO being present in said gas mixture.
Preferred embodiments of the present process are claimed in claims 6-10.
A sensor for monitoring NO in a gas mixture, a FET type element and a device for determining the NO content of an air mixture are claimed in claims 11-17, 18-20 and 21-22 respectively, and will be explained hereinafter with reference to the accompanying drawing, wherein
a is a representation of a carbon nanotube based sensor,
b is an enlarged view of an array of carbon nanotubes aligned between two metal electrodes in a carbon nanotube based sensor according to
As has been indicated above, organic field effect transistors are claimed for the detection of nitric oxide. Organic semiconducting materials can therefore be applied in a well-known conventional planar FET structure or in a nanoscale FET configuration, as will be discussed hereafter.
Conventional Planar FETs.
A planar field effect transistor (FET) is given in
Such a change in conductance is schematically represented in
Obviously, the thickness and the dopant concentration of the organic semiconducting layer are important parameters to achieve optimal sensitivity: thinner layers and low-doped or intrinsic materials, for example, will respond to lower NO concentrations, but will be more quickly “saturated”.
Nanoscale FETs.
To further improve the sensing properties of the conventional planar structure, nanoscale FETs can be used. Examples of such nanoscale devices are given in recent papers by Cui, Wei, and Lieber in Science 293, 1289 (2001) and Kong, Franklin, Zhou, Chapline, Peng, Cho, and Dai in Science 287, 622 (2000). A schematic representation of such a nanowire or nanotube sensor is given in
Nanowires may be grown by for example the so-called vapor-liquid-solid (VLS) growth method using a surface with for instance gold particles that act as catalytic growth centers, see Xiangfeng Duan and Charles, M. Lieber in Advanced Materials 12, 298 (2000). A broad range of binary and ternary III-V, II-VI, IV-IV group elements can be synthesized in this way such as GaAs, GaP, GaN, InP, GaAs/P, InAs/P, ZnS, ZnSe, CdS, CdSe, ZnO, SiGe etc. The diameter of the nanowires may be controlled on a rough scale by the size of the catalytic Au particles. If needed, fine-tuning of the diameter of the nanowires may be achieved through photochemical etching, whereby the diameter of the nanowire is determined by the wavelength of the incident light during etching.
Further, the sensitivity of the nanowire-based sensor can, if necessary, be improved by applying an organic semi-conducting layer on top of the nanowires.
Conduits 10 and 11 are connected with measuring chambers 15 and 16 respectively, which are provided with sensors as explained in
In addition, a change in the gate potential in response to the NO absorption/reaction can also be used to monitor the NO content in the air sample flowing through the measuring chamber.
Although not shown, device 9 also comprises a flow meter, necessary for airflow measurement. Further, a cooling unit may be provided upstream of the measuring chamber to remove water from the air sample to be measured. A cooling unit is not necessary however when pentacene is used as the semi-conducting compound because it is non-reactive towards water.
The sensor in measuring chamber 16 will measure the NO background in air (when air is inhaled). The sensor in measuring chamber 15 will measure the NO content of exhaled air. Measuring chambers 15 and 16 are coupled with a signal processor 17, adapted to calculate the endogenous NO production on the basis of the difference (or any other algorithms) between the reading of the sensor present in measuring chamber 15 and the reading of the sensor present in measuring chamber 16. Preliminary evidence exists that the amount of endogenous NO is not affected by the amount of atmospheric NO. In that case the measuring chamber may be omitted.
In a further modification of the present device, only the NO content of the exhaled air will be measured. Device 9 will then not comprise measuring chamber 16 and conduit 11 (this embodiment has not been shown).
From the above, it will be obvious that the electrical detection of NO using the CHEM-FET structure allows miniaturization and integration with Integrated Circuit technology.
The invention has been described by reference to certain preferred embodiments; however it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics. The embodiments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.
| Number | Date | Country | Kind |
|---|---|---|---|
| 04100851.7 | Mar 2004 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB05/50718 | 2/28/2005 | WO | 4/11/2007 |
